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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Selich, Anton Fleischauer, Jenni Roepke, Tina Weisskoeppel, Luisa Galla, Melanie von Kaisenberg, Constantin Maus, Ulrich A. Schambach, Axel Rothe, Michael |
| Abstract | Background Mesenchymal stromal cells (MSCs) are excessively investigated in the context of inflammation-driven diseases, but the clinical results are often moderate. MSCs are naturally activated by inflammatory signals, which lead to the secretion of immune inhibitory factors in inflamed tissues. Many work groups try to improve the therapeutic outcome of MSCs by genetic modification and the constitutive overexpression of immune modulatory transgenes. However, the ectopic secretion of immune inhibitory transgenes increases the chances of infections, and constitutive transgene expression is not necessary for chronic diseases undergoing different inflammatory stages. Methods We designed and tested inflammation-induced promoters to control transgene expression from integrating lentiviral vectors in human umbilical cord MSCs. Therefore, we investigated different combinations of general transcription factor elements to achieve a minimal promoter with low basal activity. The best candidates were combined with interferon-induced GAS or ISRE DNA motifs. The constructs with the highest transgene expression upon addition of pro-inflammatory cytokines were compared to vectorized promoters from inflammation-induced genes (CD317, CXCL9, CXCL10, CXCL11 and IDO1). Finally, we investigated IL10 as a potential immune inhibitory transgene by transcriptome analyses, ELISA and in an acute lung injury mouse model. Results The synthetic promoters achieved a high and specific transgene expression upon IFN-γ addition. However, the CXCL11 promoter showed synergistic activity upon IFN-γ, TNF-α and IL1-β treatment and surpassed the transgene expression height of all tested promoters in the study. We observed in transcriptome analyses that IL10 has no effect on MSCs and in ELISA that IL10 is only secreted by our genetically modified and activated CXCL11-IL10-MSCs. Finally, transplanted CXCL11-IL10-MSCs increased CD19+ and CD4+ lymphoid cells, and decreased CD11b+ Ly6g myeloid cells in an ALI mouse model. Conclusion These results provide new insights into MSC inflammatory activation and the subsequent translation into a tool for a tailored expression of transgenes in inflammatory microenvironments. The newly developed promoter elements are potentially interesting for other inflamed tissues, and can be combined with other elements or used in other cell types. |
| Related Links | https://stemcellres.biomedcentral.com/counter/pdf/10.1186/s13287-023-03501-6.pdf |
| Ending Page | 14 |
| Page Count | 14 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 17576512 |
| DOI | 10.1186/s13287-023-03501-6 |
| Journal | Stem Cell Research & Therapy |
| Issue Number | 1 |
| Volume Number | 14 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2023-09-23 |
| Access Restriction | Open |
| Subject Keyword | Stem Cells Cell Biology Regenerative Medicine Tissue Engineering Biomedical Engineering and Bioengineering Mesenchymal stromal cells Immune inhibition Genetic engineering Gene regulation Regenerative Medicine/Tissue Engineering |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Medicine Biochemistry, Genetics and Molecular Biology Molecular Medicine |
| Journal Impact Factor | 7.1/2023 |
| 5-Year Journal Impact Factor | 7.9/2023 |
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